Manipulation of NK cytotoxicity by the IAP family member Livin

Eur J Immunol. 2007 Dec;37(12):3467-76. doi: 10.1002/eji.200636600.

Abstract

Natural killer (NK) cells are part of the innate immune system, capable of killing tumor and virally infected cells. NK cells induce apoptosis in the target cell by either granule- or receptor-mediated pathways. A set of inhibitory and activation ligands governs NK cell activation. As transformed cells often attempt to evade NK cell killing, up-regulation of a potential anti-apoptotic factor should provide a survival advantage. The inhibitor of apoptosis protein (IAP) family can inhibit apoptosis induced by a variety of stimuli. We have previously described a new IAP family member, termed Livin, which has two splice variants (alpha and beta) with differential anti-apoptotic activities. In this study, we explore the ability of Livin to inhibit NK cell-induced killing. We demonstrate that Livin beta moderately protects against NK cell killing whereas Livin alpha augments killing. We show that Livin beta inhibition in Jurkat cells is apparent upon concomitant activation of an inhibitory signal, suggesting that Livin augments an extrinsic inhibitory signal rather than functioning as an independent inhibitory mechanism. Finally, we demonstrate that detection of both Livin isoforms in melanoma cells correlates with a low killing rate. To date, this is the first evidence that directly demonstrates the ability of IAP to protect against NK cell-induced apoptosis.

MeSH terms

  • Adaptor Proteins, Signal Transducing / genetics
  • Adaptor Proteins, Signal Transducing / physiology*
  • Alternative Splicing
  • Apoptosis / physiology*
  • Cell Line, Transformed / cytology
  • Cell Line, Tumor / cytology
  • Cytotoxicity, Immunologic / physiology*
  • Genes, bcl-2
  • Granzymes / metabolism
  • HLA Antigens / immunology
  • Humans
  • Inhibitor of Apoptosis Proteins / genetics
  • Inhibitor of Apoptosis Proteins / physiology*
  • Jurkat Cells / cytology
  • Killer Cells, Natural / cytology
  • Killer Cells, Natural / immunology*
  • Killer Cells, Natural / metabolism
  • Lymphocyte Activation / physiology
  • Melanoma / pathology
  • Neoplasm Proteins / genetics
  • Neoplasm Proteins / physiology*
  • Protein Isoforms / physiology
  • Protein Processing, Post-Translational
  • Proto-Oncogene Proteins c-bcl-2 / physiology
  • Receptors, KIR / physiology
  • Recombinant Fusion Proteins / physiology
  • Transduction, Genetic

Substances

  • Adaptor Proteins, Signal Transducing
  • BIRC7 protein, human
  • HLA Antigens
  • Inhibitor of Apoptosis Proteins
  • Neoplasm Proteins
  • Protein Isoforms
  • Proto-Oncogene Proteins c-bcl-2
  • Receptors, KIR
  • Recombinant Fusion Proteins
  • Granzymes